Interstitial therapy with targeted protein toxins for malignant brain tumors: We are investigating a new approach for the treatment of brain tumors which utilizes a new delivery approach for distribution of a class of potent, targeted anti-cancer compounds, called targeted protein toxins. Preclinical in vitro and in vivo experiments of toxins targeted to the transferrin receptor and epidermal growth factor (EGF) demonstrated significant antitumor activity against a variety of tumor types, including malignant gliomas. New methods of drug delivery have been developed to deliver these agents to brain tumors, and in vivo imaging methods are being developed to demonstrate drug distribution in patients. We completed a phase I trial of regional therapy with a conjugate of human transferrin (Tf) and malignant brain tumors. The results indicated that therapy with Tf-CRM107 produces tumor responses without severe neurologic or systemic toxicity. A multicenter Phase II study has now been finished. The results suggest similar efficacy and toxicity as was observed in the Phase I trial. A new protocol to investigate the safety of perfusing the region of brain surrounding tumor excision to eliminate infiltrating tumor cells and to examine the potential of protecting the brain, but not tumor, with this approach combined with systemic administration of chloroquine, an agent that inhibits endothelial cell injury by Tf-CRM 107, is being prepared. Vascular permeability factor/vascular endothelial growth factor in the CNS: Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a protein secreted by many cell types which has been shown in model systems unrelated to the central nervous system (CNS) to perform two major functions: it is an angiogenic, endothelial-specific growth factor, and a potent inducer of vascular leakage. Our continuing goal are to define the function of VEGF in the central nervous system, to understand the extent to which altered expression of VEGF contributes to the development of certain pathologic conditions, and to develop strategies for modifying the activity of VEGF in appropriate clinical settings. Recently our work has emphasized investigation of the direct effects of VEGF on normal brain. Since increased expression of VEGF and its receptors has been associated with several CNS pathologies (including brain tumors), our goals have been to understand the extent to which altered expression of VEGF contributes to the development of certain pathologic conditions involving brain edema and unregulated angiogenesis, and to develop strategies for modifying the activity of VEGF in appropriate clinical settings. The altered profile of VEGF receptors on brain tumor blood vessels allows a selective targeting of tumor-associated vessels through VEGF receptor-specific toxins. However, attempts to inhibit tumor growth by the use of VEGF-CRM107 toxin in a rodent brain tumor model were limited by damage to surrounding normal brain. In the same model, intracerebral infusion of anti-VEGF antibodies into established tumors was unable to inhibit BBB breakdown. Thus targeting the VEGF-induced vascular changes associated with brain tumors may not by itself provide effective therapy. In addition, such VEGF-related toxins or antibodies are unable to target the small infiltrative tumors not dependent on VEGF-mediated angiogenesis. Approaches to target tumor blood vessels at earlier stages of infiltrative tumor development are being sought. While studying the effects of VEGF as they relate to the tumor setting, it became apparent that VEGF also contributes to inflammation in the CNS. VEGF alone does not elicit an inflammatory response, however, VEGF can liberate an immune response to antigens already present in the CNS. VEGF potentiates inflammation in CNS not only by opening the BBB and allowing contact between normally sequestered antigens and blood-borne immune cells, but also by inducing immune mediators such as intercellular adhesion molecules and major histocompatibility complex class I and II expression in the CNS. Intracerebral administration of exogenous VEGF exacerbated neuroinflammatory lesions in the rodent EAE model of CNS autoimmune disease. The modulation of inflammation in the CNS by VEGF may have ramifications for brain tumor immunology and for inflammatory diseases of the CNS such as multiple sclerosis. Glioblastoma multiforme (GBM)after whole brain irradiation: To determine the acute and long-term effects of a therapeutic dose of whole brain radiation in a primate model, we studied the outcome in monkeys that received whole brain irradiation. Eleven male primates (Macaca mulatta) underwent fractionated (350 cGy 5 days a week for 2 weeks) whole brain irradiation (total dose 3500 cGy). Nine of the developed GBMs, which were either unifocal (n=2) or multifocal (n=7). Thus, there is a high rate of GBM formation with therapeutic doses of whole brain radiation, suggesting that radioinduction of these neoplasms in primate CNS tissue may not be an infrequent late complication of this therapy. Moreover, this infiltrative glioma model, which has histopathological characteristics identical to gliomas in humans, is being used for investigation of the anatomy and mechanism of tumor infiltration, to characterize infiltrating glioma cells, and potential therapeutic modalities. Von Hippel-Lindau disease; To define the natural history and growth pattern of central nervous system (CNS) hemangioblastomas associated with von Hippel-Lindau disease (vHL), and to correlate features of hemangioblastomas that are associated with development of symptoms and need for treatment, we reviewed serial magnetic resonance (MR)-imaging and clinical histories of 160 consecutive vHL patients with CNS hemangioblastomas and serially measured volumes of the tumors and associated cysts. 655 hemangioblastomas were identified in the cerebellum (250), brainstem (64, all in posterior medulla), spinal cord (331, 96% in posterior half of spinal cord), and the supratentorial brain (10). Twenty-one of 29 (72%) symptom-producing cerebellar tumors had an associated cyst, whereas only 28 (13%) of the 221 cerebellar tumors withousymptoms had tumor-associated cysts. Nine (75%) of 12 symptomatic brainstem tumors had associated cysts compared to only 4 (8%) of the 52 without symptoms. By the time symptoms occurred and surgery was required the cyst was larger than the tumor causing it; cerebellar and brainstem cysts averaged 34-fold and 19-fold the size of their associated tumors at surgery. Ninety-five percent of symptom-producing spinal hemangioblastomas had associated syringomyelia. No tumors or cysts spontaneously diminished in size. Symptomatic tumors grew at approximately 10-fold the rates of asymptomatic tumors and symptomatic cysts grew 3.2-fold and 1.7-fold faster than the hemangioblastomas associated with them. Hemangioblastomas frequently demonstrated a pattern of growth in which they would enlarge for a period of time (growth phase) followed by a period of arrested growth (quiescent phase). This study defined the natural history of CNS hemangioblastomas in VHL.